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1 Pediatrics, University of Colorado, Denver and Health Sciences, Denver, Colorado, United States
* To whom correspondence should be addressed. E-mail: vivek.balasubramaniam{at}uchsc.edu.
Hyperoxia disrupts vascular and alveolar growth of the developing lung and contributes to the development of bronchopulmonary dysplasia (BPD). Endothelial progenitor cells (EPC) have been implicated in repair of the vasculature but their role in lung vascular development is unknown. Since disruption of vascular growth impairs lung structure, we hypothesized that neonatal hyperoxia impairs EPC mobilization and homing to the lung, contributing to abnormalities in lung structure. Neonatal mice (1 day-old) were exposed to 80% O2 at Denver’s altitude (=65% at sea level) or room air for 10 days. Adult mice were also exposed for comparison. Blood, lung and bone marrow was harvested after hyperoxia. Hyperoxia decreased pulmonary vascular density by 72% in neonatal but not adult mice. In contrast to the adult, hyperoxia simplified distal lung structure neonatal mice. Moderate hyperoxia reduced EPCs (CD45-/Sca-1+/CD133+/VEGFR-2+) in the blood (55%;p<0.03), bone marrow (48%;p<0.01) and lungs (66%;p<0.01) of neonatal mice. EPCs increased in bone marrow (2.5-fold;p<0.01), and lungs (2.0-fold;p<0.03) of hyperoxia exposed adult mice. VEGF, nitric oxide (NO) and erythropoietin (Epo) contribute to mobilization and homing of EPCs. Lung VEGF, VEGFR-2, eNOS and EpoR expression were reduced by hyperoxia in neonatal but not adult mice. We conclude that moderate hyperoxia decreases vessel density, impairs lung structure, reduces EPCs in the circulation, bone marrow and lung of neonatal mice but increases EPCs in adults. This developmental difference may contribute to the increased susceptibility of the developing lung to hyperoxia, and may contribute to impaired lung vascular and alveolar growth in BPD.
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